Xiang Yang, Chen Cheng, Wang Wen-Ming, Xu Li-Wei, Yang Ke-Wu, Oelschlaeger Peter, He Yuan
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Laboratory, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, P. R. China.
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 East Second Street, Pomona, California 91766, United States.
ACS Med Chem Lett. 2018 Mar 22;9(4):359-364. doi: 10.1021/acsmedchemlett.7b00548. eCollection 2018 Apr 12.
A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-β-lactamases (MβLs) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the MβL L1 with an IC range of 0.02-1.7 μM, and compounds - exhibited broad-spectrum inhibition of the MβLs NDM-1, VIM-2, ImiS, and L1 with IC values <16 μM. All inhibitors increased the antimicrobial effect of cefazolin against cells expressing L1, resulting in a 2-8-fold reduction in MIC. Docking studies suggested that the nitro (NDM-1, CphA, and L1) or carboxyl group (VIM-2) of coordinates one or two Zn(II) ions, while the -phenyl group of the inhibitor enhances its hydrophobic interaction with MβLs. These studies demonstrate that the diaryl-substituted rhodanines are good scaffolds for the design of future broad-spectrum inhibitors of MβLs.
构建了一系列若丹宁，通过小分子X射线晶体结构确认了它们的Z构型，并测定了它们对金属β-内酰胺酶（MβLs）的活性。所得到的26个分子和一种硫醇盐特异性抑制MβL L1，IC范围为0.02 - 1.7 μM，并且化合物对MβLs NDM-1、VIM-2、ImiS和L1表现出广谱抑制，IC值<16 μM。所有抑制剂均增强了头孢唑林对表达L1的细胞的抗菌作用，导致MIC降低2 - 8倍。对接研究表明，的硝基（NDM-1、CphA和L1）或羧基（VIM-2）与一个或两个Zn(II)离子配位，而抑制剂的-苯基增强了其与MβLs的疏水相互作用。这些研究表明，二芳基取代的若丹宁是设计未来MβLs广谱抑制剂的良好支架。
